Ebola (EBOV) and Marburg (MARV) viruses belong to the family Filoviridae and can cause fatal hemorrhagic fevers characterized by widespread tissue destruction with an incubation period of 4-14 days. Because of the safety concerns, these viruses are designated as biosafety level 4 agents. Currently there is no effective vaccine or therapeutic treatment against filoviral infection and pathogenesis in humans. The current ongoing 2014 Ebola epidemic in West Africa has led to more than 5,000 deaths and underscores the global challenge of treating and controlling this deadly virus. This application defines a plan to identify and develop potent small molecule inhibitors, which block entry of EBOV into host cells. We have developed a cell-based HTS protocol targeting Ebola entry to identify small molecule inhibitors that block entry of infectious EBOV. The overall objective of this Phase I application is to identify and develop these inhibitors as potential anti-Ebola therapeutics. This application will focus on the following three specific aims: (1) Identify potent anti-Ebola inhibitors from a small molecule library of GPCR antagonists, prioritize and chemically modify the most potent inhibitors based on structure-activity relationships (SARs) to improve potency and selectivity. (2) Validate the lead inhibitor candidates in the infectious assay and investigate the mechanism of action (MOA) of the EBOV inhibitors. (3) Select EBOV inhibitors with in vitro ADME properties suitable for i.v. and oral dosing.